Natto Manal J, Hulpia Fabian, Kalkman Eric R, Baillie Susan, Alhejeli Amani, Miyamoto Yukiko, Eckmann Lars, Van Calenbergh Serge, de Koning Harry P
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, U.K.
Laboratory for Medicinal Chemistry, Campus Heymans (FFW), Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium.
ACS Infect Dis. 2021 Jun 11;7(6):1752-1764. doi: 10.1021/acsinfecdis.1c00075. Epub 2021 May 11.
Trichomoniasis is the most common nonviral sexually transmitted disease in humans, but treatment options are limited. Here, we report a resorufin-based drug sensitivity assay for high-throughput microplate-based screening under hypoxic conditions. A 5203-compound enamine kinase library and several specialized compound series were tested for the inhibition of growth at 10 μM with ' values of >0.5. Hits were rescreened in serial dilution to establish an IC concentration. A series of 7-substituted 7-deazaadenosine analogues emerged as highly potent anti-. agents, with EC values in the low double digit nanomolar range. These analogues exhibited excellent selectivity indices. Follow-up medicinal chemistry efforts identified an optimal ribofuranose and C7 substituent. Several nucleosides rapidly cleared cultures of . at a concentrations of just 2 × EC. Preliminary evaluation in a murine trichomoniasis model () revealed promising activity upon topical administration, validating purine nucleoside analogues as a new class of antitrichomonal agents.
滴虫病是人类最常见的非病毒性性传播疾病，但治疗选择有限。在此，我们报告了一种基于试卤灵的药物敏感性测定法，用于在缺氧条件下基于微孔板的高通量筛选。测试了一个包含5203种化合物的烯胺激酶文库和几个特定化合物系列对生长的抑制作用，浓度为10μM，‘值>0.5。对筛选出的阳性结果进行系列稀释再筛选，以确定IC浓度。一系列7-取代的7-脱氮腺苷类似物成为高效抗滴虫剂，其EC值在低两位数纳摩尔范围内。这些类似物表现出优异的选择性指数。后续的药物化学研究确定了最佳的呋喃核糖和C7取代基。几种核苷在仅2×EC的浓度下就能迅速清除滴虫培养物。在小鼠滴虫病模型中的初步评估显示，局部给药时有良好的活性，证实嘌呤核苷类似物是一类新型抗滴虫剂。
